The natural hormone, 1α,25-dihydroxyvitamin D3 and its analog in the ergosterol series (i.e., 1α,25-dihydroxyvitamin D2) are potent regulators of calcium homeostasis in animals and humans. Recently, its cellular differentiation activity has been established, see Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Structural analogs of these metabolites have been prepared and tested such as 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, and, various side-chain homologated vitamins and fluorinated analogs thereof. Some of these compounds exhibit separation of activities in cell differentiation and calcium regulation. The difference in activity may be advantageous in treating a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and other malignancies.
A class of vitamin D analogs, the 19-nor-vitamin D compounds, are characterized by replacement of the A-ring exocyclic methylene group at the carbon 19 (typical of the vitamin D system) with two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D3) revealed a selective activity profile having high potency to induce cellular differentiation and very low calcium mobilizing activity. Potentially, these compounds are useful therapeutic agents for treating renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, other malignancies and various skin disorders.
Two different synthetic methods of making various 19-nor-vitamin D analogs have been described—See Perlman et al., Tetrahedron Letters 31, 1823 (1990); Perlman et al., Tetrahedron Letters 32, 7663 (1991); and, DeLuca et al., U.S. Pat. No. 5,086,191. Analogs of 1α,25-dihydroxy-19-norvitamin D3 substituted at 2-position with hydroxy or alkoxy groups have also been synthesized (see DeLuca et al., U.S. Pat. No. 5,536,713) which may exhibit selective activity profiles.
Analogs characterized by the transposition of the A-ring exocyclic methylene group from carbon 10 (C10) to carbon 2 (C2) (e.g., 2-methylene-19-nor-vitamin D compounds) have been synthesized and tested. (See Sicinski et al., J. Med. Chem., 41, 4662 (1998); Sicinski et al., Steroids 67, 247 (2002); and, DeLuca et al., U.S. Pat. Nos. 5,843,928; 5,936,133 and 6,382,071). Molecular mechanics studies performed on these analogs predict that a change of A-ring conformation may cause flattening of the cyclohexanediol ring. Molecular mechanics calculations and NMR studies also predict that the A-ring conformational equilibrium would be ca. 6:4 in favor of the conformer having an equatorial 1α-OH. It was further predicted that introduction of the 2-methylene group into 19-nor-vitamin D carbon skeleton would change the character of its 1α- and 3β-A-ring hydroxyls. They would both be in allylic positions similar to the 1α-hydroxyl group (which is important for biological activity) in the molecule of the natural hormone (i.e., 1α,25-(OH)2D3). It was found that 1α,25-dihydroxy-2-methylene-19-norvitamin D analogs are characterized by significant biological potency. In addition, the biological potency of such analogs may be enhanced dramatically where “unnatural” (20S) configuration is present.
Recently, 2-ethylidene analogs of 1α,25-dihydroxy-19-norvitamin D3 have been synthesized whereby such modification of the A-ring resulted in significant biological potency particularly for the E-geometrical isomers, see Sicinski et al., J. Med. Chem., 45, 3366 (2002). It has been established that E-isomers have A-ring conformational equilibrium that is considerably shifted to the chair form possessing 1α-hydroxyl in equatorial orientation.
Recently, derivatives of 1α,25-dihydroxy-19-norvitamin D3 having a 3′-hydroxypropylidene moiety at C-2 have been synthesized (see DeLuca et. al, U.S. Patent Application No. 2004/0229851) whereby the in vivo calcemic activity significantly exceeded that of 1α,25-(OH)2D3 particularly regarding stimulation of intestinal calcium transport. Molecular modeling studies of the analogs predicted that presence of an oxygen function (located at the terminus of the propylidene fragment) may promote interaction with the vitamin D receptor. The modeling further predicted that affinity of the synthesized compounds to VDR may approach that of the natural hormone. Taking into account the recent findings on 2-methylene-1α-hydroxy-19-norvitamin D analogs having truncated side-chains, Plum et al., PNAS, 101, 6900 (2004), indicates that such compounds effectively suppress parathyroid hormone levels.